AIKO Biotechnology, Inc. is a start-up biotechnology company focused on developing safe and effective therapeutics for the management of pain and addiction. Opioid drugs are the standard of care in the treatment of pain. However, opioids produce a spectrum of adverse effects, including opioid-induced bowel dysfunction, that limit their clinical utility. Opioid antagonists have shown efficacy in reducing unwanted side-effects, but the antagonists themselves cause serious side effects (e.g., excessive abdominal cramping). Based on a new understanding of opioid receptor pharmacology, AIKO scientists have developed and patented the use of 'neutral' opioid antagonists that block the unwanted actions of opioid drugs, but have significantly lower side effects than currently used opioid antagonists. Results from this project will establish the feasibility of developing a lead drug candidate that is a peripherally-selective, long-acting neutral antagonist expected to block the unwanted peripherally mediated opioid side effects while preserving analgesic actions. Specific aims include: (i) determining the relative selectivity of the neutral antagonist for peripheral vs. central opioid receptors to define a therapeutic dosage range that relieves peripheral side effects without inhibiting analgesia; (ii) comparing the opioid withdrawal precipitated by the neutral antagonist to other antagonists under development showing that the AIKO neutral antagonist evokes limited adverse side effects; and (iii) determining the maximum tolerated doses (acute and sub-chronic) of the AIKO neutral antagonist as an early indication of its safety and tolerability for humans. Research will be conducted using established rodent models and procedures for evaluation of opioid pharmacology. These data are critical for discussions with the Food and Drug Administration that will lead to successful clinical trial design and an Investigational New Drug Application. This research addresses a significant problem with opioid analgesics, which solution will provide better management of addiction, treatment of acute and chronic pain, and relief from opioid-induced bowel dysfunction. Successful development of a neutral opioid antagonist will lead to safer, more efficacious pain and addiction management that is needed by millions of people each year. Opioid analgesics remain the standard of care for moderate to severe, acute and chronic pain, and are prescribed for millions of people each year. The use of opioids leads to adverse effects including opioid-induced bowel dysfunction (e.g., severe constipation, nausea and vomiting) and post-operative ileus. AIKO Biotechnology will determine the feasibility of using its proprietary peripherally restricted opioid neutral antagonist for treatment of adverse opioid effects, thereby decreasing morbidity and mortality associated with pain management. [unreadable] [unreadable] [unreadable]